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Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.

Kim J, Sato M, Choi JW, Kim HW, Yeh BI, Larsen JE, Minna JD, Cha JH, Jeong Y - PLoS ONE (2015)

Bottom Line: Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs.In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner.Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.

ABSTRACT
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.

No MeSH data available.


Related in: MedlinePlus

Expression profile of the NR superfamily in tumorigenic HBEC clones.The QPCR assay was performed for mRNA expression of the entire NR superfamily in non-tumorigenic HBEC-KTRL53 cells with p53 and K-rasV12 changes, two tumorigenic clones C1 and C5, and xenograft C5 tumor tissue. (A) Quantitative mRNA expression profiles of the NR subgroups with distinct expression pattern across the panel. Note that the rest of the NR profile was shown in S4 Fig. (B) Summary of NR expression from panel A and Fig 2 to show NR expression cascades correlated with tumorigenic progression. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KTRL53.
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pone.0134842.g005: Expression profile of the NR superfamily in tumorigenic HBEC clones.The QPCR assay was performed for mRNA expression of the entire NR superfamily in non-tumorigenic HBEC-KTRL53 cells with p53 and K-rasV12 changes, two tumorigenic clones C1 and C5, and xenograft C5 tumor tissue. (A) Quantitative mRNA expression profiles of the NR subgroups with distinct expression pattern across the panel. Note that the rest of the NR profile was shown in S4 Fig. (B) Summary of NR expression from panel A and Fig 2 to show NR expression cascades correlated with tumorigenic progression. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KTRL53.

Mentions: Since PPARγ expression was remarkably suppressed in the fully malignant HBECs, we wondered if any other NRs are differently expressed with the same tumorigenic progression. Thus, we completed the mRNA expression profile of the entire NR superfamily in the panel of non-tumorigenic HBEC-KTRL53 cells and the tumorigenic clonal derivatives including tumorigenic cell lines established from C1 and C5 tumors, and C5 tumor itself (Fig 5A and S4 Fig). Fifteen of the 50 NRs showed expression patterns potentially associated with the malignant progression of HBEC-KTRL53 cells into HBEC tumors (Fig 5A). Included in this group were AR, Coup-TFα, Coup-TFβ, dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX1), ERα, ERRα, HNF4γ, liver receptor homolog-1 (LRH1), NOR1, NURR1, PPARγ, RARβ, RORα, RORβ, and VDR (Fig 5A). Interestingly, nine out of the 15 NRs (AR, Coup-TFα, DAX1, HNF4γ, LRH1, NOR1, NURR1, RORα, and RORβ) showed continuously increasing expression pattern upon tumorigenic progression (Fig 5B). AR and DAX1 showed dramatically increased expression only in HBEC tumors, but not in the immortalized HBEC cell lines. ERRα and VDR showed decreased expression during tumorigenesis from non-oncogenic HBEC-KT, through HBEC-KTRL53 to HBEC tumors (Fig 5B). Coup-TFβ, ERα, and RARβ showed a biphasic expression pattern, where the initial expression of the NRs in HBEC-KT decreased in HBEC-KTRL53, but rebounded in HBEC tumors, which is opposite to the complete loss of PPARγ expression in HBEC tumors (Fig 5B). More interestingly, adenocarcinoma type HBEC-C5 cells and tumor, but not the squamous cell carcinoma HBEC-C1, showed increased expression of Coup-TFα and β, and decreased expression of ERRα and VDR, suggesting that these four NRs might be specifically involved in adenocarcinoma type-specific lung cancer pathogenesis.


Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.

Kim J, Sato M, Choi JW, Kim HW, Yeh BI, Larsen JE, Minna JD, Cha JH, Jeong Y - PLoS ONE (2015)

Expression profile of the NR superfamily in tumorigenic HBEC clones.The QPCR assay was performed for mRNA expression of the entire NR superfamily in non-tumorigenic HBEC-KTRL53 cells with p53 and K-rasV12 changes, two tumorigenic clones C1 and C5, and xenograft C5 tumor tissue. (A) Quantitative mRNA expression profiles of the NR subgroups with distinct expression pattern across the panel. Note that the rest of the NR profile was shown in S4 Fig. (B) Summary of NR expression from panel A and Fig 2 to show NR expression cascades correlated with tumorigenic progression. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KTRL53.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526668&req=5

pone.0134842.g005: Expression profile of the NR superfamily in tumorigenic HBEC clones.The QPCR assay was performed for mRNA expression of the entire NR superfamily in non-tumorigenic HBEC-KTRL53 cells with p53 and K-rasV12 changes, two tumorigenic clones C1 and C5, and xenograft C5 tumor tissue. (A) Quantitative mRNA expression profiles of the NR subgroups with distinct expression pattern across the panel. Note that the rest of the NR profile was shown in S4 Fig. (B) Summary of NR expression from panel A and Fig 2 to show NR expression cascades correlated with tumorigenic progression. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KTRL53.
Mentions: Since PPARγ expression was remarkably suppressed in the fully malignant HBECs, we wondered if any other NRs are differently expressed with the same tumorigenic progression. Thus, we completed the mRNA expression profile of the entire NR superfamily in the panel of non-tumorigenic HBEC-KTRL53 cells and the tumorigenic clonal derivatives including tumorigenic cell lines established from C1 and C5 tumors, and C5 tumor itself (Fig 5A and S4 Fig). Fifteen of the 50 NRs showed expression patterns potentially associated with the malignant progression of HBEC-KTRL53 cells into HBEC tumors (Fig 5A). Included in this group were AR, Coup-TFα, Coup-TFβ, dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX1), ERα, ERRα, HNF4γ, liver receptor homolog-1 (LRH1), NOR1, NURR1, PPARγ, RARβ, RORα, RORβ, and VDR (Fig 5A). Interestingly, nine out of the 15 NRs (AR, Coup-TFα, DAX1, HNF4γ, LRH1, NOR1, NURR1, RORα, and RORβ) showed continuously increasing expression pattern upon tumorigenic progression (Fig 5B). AR and DAX1 showed dramatically increased expression only in HBEC tumors, but not in the immortalized HBEC cell lines. ERRα and VDR showed decreased expression during tumorigenesis from non-oncogenic HBEC-KT, through HBEC-KTRL53 to HBEC tumors (Fig 5B). Coup-TFβ, ERα, and RARβ showed a biphasic expression pattern, where the initial expression of the NRs in HBEC-KT decreased in HBEC-KTRL53, but rebounded in HBEC tumors, which is opposite to the complete loss of PPARγ expression in HBEC tumors (Fig 5B). More interestingly, adenocarcinoma type HBEC-C5 cells and tumor, but not the squamous cell carcinoma HBEC-C1, showed increased expression of Coup-TFα and β, and decreased expression of ERRα and VDR, suggesting that these four NRs might be specifically involved in adenocarcinoma type-specific lung cancer pathogenesis.

Bottom Line: Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs.In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner.Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.

ABSTRACT
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.

No MeSH data available.


Related in: MedlinePlus